The present invention relates to pyrrolopyridazine compounds, the methods of preparation of these compounds, and their use in the treatment of conditions in which selective modulation of the JAK signaling pathway via inhibition of the Janus kinases (JAKs) kinases, particularly the JAK3 kinase, may be therapeutically beneficial.
The Janus kinases (JAKs) belong to the non-receptor protein tyrosine kinase family and are known to be critical intracellular regulators of cytokine signaling via modulation of the JAK-STAT pathway (see, Murray, P. J., Immunity, 28:763 (2008)). There are four known mammalian JAK isoforms which include JAK1, JAK2, JAK3 and TYK2.
JAK3 has been shown to play a specific role in the signaling of a subset of cytokines known as the gamma common chain cytokine family which includes the interleukins IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Deficiency of JAK3 in rodents and humans results in a severe combined immunodeficient (SCID) phenotype (see, Pesu, M. et al., Immunol. Rev., 203:127 (2005)). Furthermore, JAK3 is known to have limited expression in hematopoeitic cells whereas JAK1, JAK2 and TYK2 have been shown to be more ubiquitously expressed. As a result of its specific role in regulating the immune response and its localized expression in lymphoid cells, inhibition of JAK3 has been recognized as a promising strategy for the development of novel and selective immunosuppressive agents that may be useful for transplant rejection prevention and in the treatment of autoimmune and inflammatory diseases such as psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, and lupus (see, O'Shea, J. J. et al., Nat. Rev. Drug Discov., 3(7):555 (2004)). Moreover, the JAK inhibitor, CP-690,550 which potently inhibits JAK3, has been reported to be effective in the treatment of arthritis in rodent models as well as in patients with rheumatoid arthritis (see, Milici, A. J. et al., Arthritis Res. & Therapy, R14 (2008) and Coombs, J. H. et al., Ann. Rheum. Dis., 69:413 (2010)). It has been suggested that the clinical efficacy of CP-690,550 (Tofacitinib) may be related to its ability to inhibit other JAK family members (see Ghoreschi, K. et al., J. Immunol., 186:4234 (2011)). While JAK3 and JAK1 are both capable of modulating gamma common chain induce phosphorylation of STAT signalling, JAK1 inhibition can also decrease non-gamma common chain cytokine signalling (e.g., IL-6 signalling). Accordingly, novel compounds which inhibit the JAK/STAT pathway, more particularly via selective inhibition of JAK3 and/or JAK1, may be therapeutically useful. Certain inhibitors of JAK3 have been disclosed in applications filed by the present applicant via the Patent Cooperation Treaty under Nos. PCT/US2012/029334, PCT/US2012/029366 and PCT/US2012/029337.
It should be noted that the closely related isoform JAK2, is classically associated with interferon-γ production through the IL-12 pathway, but it also mediates the signaling of important hematopoietic growth factors such as erythropoietin (EPO), thromobopoetin (TPO) and granulocyte macrophage-stimulating factor (GM-CSF). As a result, the inhibition of JAK2 may result in adverse hematopoietic effects such as anemia, thrombocytopenia and generalized leukopenia.
Therefore, novel compounds which selectively inhibit JAK3 and/or JAK1 over JAK2 may be especially desirable in the safe treatment of chronic inflammatory and autoimmune diseases.